title: VEGFR1 and PKCα signaling control melanoma vasculogenic mimicry in a VEGFR2 kinase-independent manner.
abstract: We have recently shown that vascular endothelial growth factor-A (VEGFA), a major regulator of tumor vascularization, is essential for the organization of tumor cells into capillary-like structure (CLS), which is a hallmark of tumor vasculogenic mimicry (VM). Herein we further dissect the involvement of VEGFA and its downstream transducers, VEGF receptor 1 (VEGFR1), VEGFR2, and protein kinase C (PKC) in melanoma VM. The knockdown of VEGFR1 in three melanoma cell lines completely disrupts Matrigel-induced CLS formation, whereas inhibition of VEGFR2 kinase with a specific inhibitor, protein tyrosine kinase inhibitor II (PTKi-II), does not affect the process, indicating that VEGFR2 signaling is not involved in VEGFA-mediated melanoma VM. Furthermore, among tested PKC isoforms, only PKCα and δ are expressed in the melanoma cells during CLS formation. Pretreatment with selective PKCα and δ inhibitors blocked CLS formation. However, inhibition of PKCα, but not PKCδ, completely destroyed the previously formed CLS. Moreover, knockdown of PKCα, but not PKCδ, using small interfering RNAs abrogated CLS formation, suggesting that PKCα is the major contributory factor in melanoma VM. In-vivo experiments indicate that disruption of PKCα signaling significantly reduces the signs of VM in allografted B16/F10 melanoma. These findings may contribute to the development of new therapeutic agents that target melanoma VM.
authors.affiliation: N.N. Blokhin Russian Cancer Research Center, Russian Academy of Medical Sciences, Kashirskoye Shosse 24,Moscow, Russia. zhivotov57@mail.ru
authors.forename: Amalia
authors.initials: A
authors.lastname: Vartanian
authors.forename: Eugenia
authors.initials: E
authors.lastname: Stepanova
authors.forename: Irina
authors.initials: I
authors.lastname: Grigorieva
authors.forename: Elico
authors.initials: E
authors.lastname: Solomko
authors.forename: Anatoly
authors.initials: A
authors.lastname: Baryshnikov
authors.forename: Mikhail
authors.initials: M
authors.lastname: Lichinitser
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008545:Melanoma / Q000098:blood supply* / Q000201:enzymology / Q000473:pathology; D008546:Melanoma, Experimental / Q000098:blood supply / Q000201:enzymology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic / Q000201:enzymology* / Q000473:pathology; D051571:Protein Kinase C-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011758:Pyrroles / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000098:blood supply* / Q000201:enzymology / Q000473:pathology; D014162:Transfection; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism*
chemical_list: D007211:Indoles; D011758:Pyrroles; D034741:RNA, Small Interfering; C085989:Ro 32-0432; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2; D051571:Protein Kinase C-alpha